Annual Report of Cosmetology vol.4, 1996
Synopsis of Original Research Paper

Development of Theoritical Design for Skin Penetration
Enhancement of Drugs
Mitsuru Hashida
Faculty of Pharmaceutical Sciences, Kyoto University

Effectiveness of prodrug-enhancer combination for enhancement of skin penetrationof drugs is proposed and confirmed in this study. Based on a skin diffusion model, we
hypothesized that skin permeation of drug could be the most effectively enhanced byderivatizing into a prodrug with the optimal lipophilicity for the enhancer, when its action
mechanism is elucidated in the same model. Employing acyclovir as a model drug, thehypothesis was proved by synthesizing seven types of its prodrugs and evaluating their in vitro
permeation in rat skin, pretreated with 1-geranylazacycloheptan-2-one (GACH), a penetration
enhancer. Among seven prodrugs, those with higher lipophilicities (propionate, butyrate,valerate, and hexanoate isovalerate, pivarate prodrugs) showed larger enhancement in theirskin penetration than those of hydrophilic ones (acetate and acyclovir), when administrated in
combination of GACH. In this approach, prodrugs applied topically were metabolized throughthe skin, since skin was metabolically active tissues. We have proposed that a two-layer
skin diffusion model with polar and nonpolar route in the stratum corneum, which included
metabolic process in the viable epidermis and dermis, could comprehensively account for skinpermeation of acyclovir prodrugs. Concerning the effect of GACH, the estimated partition
parameters of prodrugs in the nonpolar route increased with an increase in pretreatment
dose of GACH, but their diffusivities were little affected being in good agreement with thetheoretical prediction. In addition, GACH was significantly decreased the enzymatic hydrolysis
rate constants of all prodrugs in the skin. These experiments have been studied with an in vitro
condition, and a goal of in vitro studies is the prediction of in vivo absorption behavior. We
previously demonstrated quantitative in vitro/in vivo differences in skin penetration in termsof diffusion and partition parameters. However it has not been established these differences
concerning metabolic process. So we demonstrated to quantitate in vitro/in vivo differences inskin penetration and bioconversion of acyclovir prodrugs. In order to confirm the possibilityof this combination approach with an in vivo condition, penetration profiles was evaluated bya deconvolution method which enabled to estimate first-pass metabolism. Next we analyzed invivo skin urinary excretion profile based on a diffusion/bioconversion model, and diffusion,
partition and metabolic parameters were compared between in vitro and in vivo condition.
In conclusion, skin permeation of prodrugs applied with an enhancer can be predictedand optimized based on a model analysis. This combined approach would be applicable to awide range of drugs, since extreme alteration of physicochemical properties of drugs is notnecessary as is the case of single prodrug application.

The Cosmetology Research Foundation
http://cosmetology.or.jp/en/

Nichitoha-Hatchobori bldg. 5F, 3-11-8 Hatchobori, Chuo-ku, Tokyo 104-0032, Tokyo